The present invention relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptides and analogs thereof, pharmaceutical compositions containing such peptides and methods for using these peptides in the treatment of HCV infection. This invention further relates to method for the synthesis of these peptide analogs and intermediates therefor.
Hepatitis C virus (HCV) is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 150 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis. However, the Center for Disease Control does not presently recommend immunoglobulins for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.
Various clinical studies have been conducted with the goal of identifying pharmaceutical agents capable of effectively treating HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone and in combination with other antiviral agents. Such studies have shown that a substantial number of the participants do not respond to these therapies, and of those that do respond favorably, a large proportion were found to relapse after termination of treatment.
Until recently, interferon (IFN) was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Recently, interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone. However, the side effects caused by IFN are not alleviated with this combination therapy.
Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.
HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading trame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one, as yet poorly characterized, cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (henceforth referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV. A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus. In this vein, patent application WO 97/06804 describes the (xe2x88x92) enantiomer of the nucleoside analogue cytosine-1,3-oxathiolane (also known as 3TC) as active against HCV. This compound, although reported as safe in previous clinical trials against HIV and HBV has yet to be clinically proven active against HCV and its mechanism of action against the virus has yet to be reported.
Intense efforts to discover compounds which inhibit the NS3 protease or RNA helicase of HCV have led to the following disclosures:
U.S. Pat. No. 5,633,388 describes heterocyclic-substituted carboxamides and analogues as being active against HCV. These compounds are directed against the helicase activity of the NS3 protein of the virus but clinical tests have not yet been reported.
A phenanthrenequinone has been reported by Chu et al (Tet. Lett., (1996), 7229-7232) to have activity against the HCV NS3 protease in vitro. No further development on this compound has been reported.
A paper presented at the Ninth International Conference on Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research, 30, 1, 1996; A23 (abstract 19)) reports thiazolidine derivatives to be inhibitory to the HCV protease.
Several studies have reported compounds inhibitory to other serine proteases, such as human leukocyte elastase. One family of these compounds is reported in WO 95/33764 (Hoechst Marion Roussel, 1995). The peptides disclosed in that application are morpholinylcarbonyl-benzoyl-peptide analogues that are structurally different from the peptides of the present invention.
WO 98/17679 from Vertex Pharmaceuticals Inc. discloses inhibitors of serine protease, particularly, Hepatitis C virus NS3 protease. These inhibitors are peptide analogues based on the NS5A/5B natural substrate that contain C-terminal activated carbonyl function as an essential feature. These peptides were also reported to be active against other serine protease and are therefore not specific for HCV NS3 protease.
Hoffman LaRoche has also reported hexapeptides that are proteinase inhibitors useful as antiviral agents for the treatment of HCV infection. These peptides contain an aldehyde or a boronic acid at the C-terminus.
Steinkxc3xchler et al. and Ingallinella et al. have published on NS4A-4B product inhibition (Biochemistry (1998), 37, 8899-8905 and 8906-8914). However, the peptides and peptide analogues presented do not include nor do they lead to the design of the peptides of the present invention.
WO 98/46597 from Emory University discloses serine proteace inhibitors. particularly Hepatitis C virus protease. All of the compounds disclosed are structurally different from the peptides of the present invention.
WO 98/46630 from Peptide Therapeutics Ltd. discloses hepatitis C NS3 protease inhibitors. However, none of the peptides disclosed are related to the peptides of the invention.
JP10298151 from Japan Energy Corp. discloses N-(2,3-dihydroxybenzoyl)-substituted serine derivatives as serine protease inhibitors, specifically as hepatitis C viral protease inhibitors. These compounds do not contain any structural similarity to the peptide analogs of the present invention.
One advantage of the present invention is that it provides peptides that are inhibitory to the NS3 protease of the hepatitis C virus.
A further advantage of one aspect of the present invention resides in the fact that these peptides specifically inhibit the NS3 protease and do not show significant inhibitory activity at concentrations up to 300 xcexcM against other serine proteases such as human leukocyte elastase (HLE). porcine pancreatic elastase (PPE). or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B (Cat B).
We investigated peptides potentially inhibitory to the NS3 protease. The discovery that the N-terminal cleavage product (Ac-D-D-I-V-P-C-OH) [SEQ. ID NO. 1] of an analog of a natural substrate of the NS3 protease was inhibitory led us to the peptide analogs of the present invention.
Included in the scope of the invention are racemates, diastereoisomers and optical isomers of compounds of formula (I): 
wherein Q is CH2 or Nxe2x80x94Y wherein Y is H or C1-6 alkyl;
a) when Q is CH2, a is 0, b is 0, then B is an amide derivative of formula R11aN(R11b)xe2x80x94C(O)xe2x80x94 wherein R11a, is H; C1-10 alkyl; C6 aryl; C7-10 alkylaryl; C3-7 cycloalkyl or C4-8 (alkylcycloalkyl) optionally substituted with carboxyl; or heterocycle-C1-6 alkyl such as 
and R11b is C1-6 alkyl substituted with carboxyl, (C1-6 alkoxy)carbonyl or phenylmethoxycarbonyl; or C7-16 aralkyl substituted on the aromatic portion with carboxyl, (C1-6 alkoxy)carbonyl or phenylmethoxycarbonyl;
or R11a and R11b are joined to form a 3 to 7-membered nitrogen-containing ring optionally substituted with carboxyl or (C1-6 alkoxy) carbonyl; or
b) when Q is Nxe2x80x94Y, a is 0 or 1, b is 0 or 1, then
B is H, an acyl derivative of formula R11xe2x80x94C(O)xe2x80x94 or a sulfonyl of formula R11xe2x80x94SO2 wherein
R11 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy (e.g.
AcOCH2xe2x80x94), C1-6 alkoxy (e.g. Boc), or carboxyl substituted with 1 to 3 C1-6 alkyl substituents:
(ii) C3-7 cycloalkyl or C4-10 alkylcycloalkyl, both optionally substituted with carboxyl 
xe2x80x83(C1-6 alkoxy)carbonyl or phenylmethoxycarbonyl;
(iii) C6 or C10 aryl or C7-16aralkyl optionally substituted with C1-6 alkyl, hydroxy, or amino optionally substituted with C1-6 alkyl; or
(iv) Het optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, or amido optionally substituted with C1-6 alkyl, or 
xe2x80x83R6 when present, is
C1-6 alkyl substituted with carboxyl;
R5, when present, is C1-6 alkyl optionally substituted with carboxyl: or
c) when Q is either CH2 or Nxe2x80x94Y, then
R4 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
Z is oxo or thioxo;
R3 is C1-10 alkyl optionally substituted with carboxyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
W is a group of formula II: 
wherein R2 is C1-10 alkyl or C3-10 cycloalkyl optionally substituted with carboxyl or an ester or amide thereof; C6 or C10 aryl or C7-16aralkyl; or
W is a group of formula IIa: 
wherein X is CH or N; and
R2a is divalent C3-4 alkylene which together with X and the carbon atom to which X and R2a are attached form a 5- or 6-membered ring, said ring optionally substituted with OH; SH; NH2; carboxyl; R12; CH2xe2x80x94R12, OR12, C(O)OR12, SR12, NHR12 or NR12R12a:
wherein R12 and R12a are independently a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R15,
or R12 and R12a is a C6 or C10 aryl or C7-16aralkyl optionally mono-, di- or tri-substituted with R15, or R12 and R12a is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R15,
wherein each R15 is independently C1-6 alkyl; C1-6 alkoxy: amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; carboxyli, carboxy(lower alkyl): C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl aralkyl or Het being optionally substituted with R16:
wherein R16 is C1-6 alkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl: NO2; OH; SH; halo; haloalkyl; carboxyl; amide; or (lower alkyl)amide;
or X is CH or N; and R2a, is a divalent C3-4 alkylene which together with X and the carbon atom to which X and R2a are attached form a 5- or 6-membered ring which in turn is fused with a second 5-, 6- or 7-membered ring to form a bicyclic system wherein the second ring is substituted with OR12a wherein R12a is C7-16 aralkyl; R1a is hydrogen, and R1 is C1-6 alkyl optionally substituted with thiol or halo; or R1 is C2-6 alkenyl; or
R1a and R1 together form a 3- to 6-membered ring optionally substituted with R14 wherein R14 is C1-6 alkyl, C3-5 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6 aryl or C7-10 aralkyl all optionally substituted with halo; and
A is hydroxy or a N-substituted amino;
or a pharmaceutically acceptable salt or ester thereof.
Included within the scope of this invention is a pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.
An important aspect of the invention involves a method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I, or a therapeutically acceptable salt or ester thereof or a composition as described above.
Another important aspect involves a method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I, or a therapeutically acceptable salt or ester thereof or a composition as described above.
Still another aspect involves a method of treating a hepatitis C viral infection in a mammal by administering thereto an anti-hepatitis C virally effective amount of a combination of the compound of formula I, or a therapeutically acceptable salt or ester thereof, and an interferon. A pharmaceutical composition comprising the combination in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent is also within the scope of this invention.
As used herein, the following definitions apply unless otherwise noted: With reference to the instances where (R) or (S) is used to designate the configuration of a radical, e.g. R4 of the compound of formula I, the designation is done in the context of the compound and not in the context of the radical alone. The natural amino acids, with exception of glycine, contain a chiral carbon atom. Unless otherwise specifically indicated, the compounds containing natural amino acids with the L-configuration are preferred. However, applicants contemplate that when specified, some amino acids of the formula I can be of either D- or L-configuration or can be mixtures of D- and L-isomers, including racemic mixtures.
The designation xe2x80x9cP1, P2, P3 et.xe2x80x9d as used herein refer to the position of the amino acid residues starting from the C-terminus end of the peptide analogues and extending towards the N-terminus (i.e. P1 refers to position 1 from the C-terminus, P2: second position from the C-terminus, etc.) (see Berger A. and Schechter I., Transactions of the Royal Society London series B257, 249-264 (1970)).
The abbreviations for the at-amino acids are set forth in Table A.
As used herein the term xe2x80x9caminobutyric acidxe2x80x9d refers to a compound of formula: 
As used herein the term xe2x80x9callylglycinexe2x80x9d refers to a compound of formula: 
As used herein the term xe2x80x9c1-aminocyclopropyl-carboxylic acidxe2x80x9d (Acca) refers to a compound of formula: 
As used herein the term xe2x80x9ctert-butylglycinexe2x80x9d refers to a compound of formula: 
The term xe2x80x9cresiduexe2x80x9d with reference to an amino acid or amino acid derivative means a radical derived from the corresponding xcex1-amino acid by eliminating the hydroxyl of the carboxy group and one hydrogen of the xcex1-amino group. For instance, the terms Gln, Ala, Gly, Ile, Arg, Asp, Phe, Ser, Leu, Cys, Asn, Sar and Tyr represent the xe2x80x9cresiduesxe2x80x9d of L-glutamine, L-alanine, glycine, L-isoleucine, L-arginine, L-aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively.
The term xe2x80x9cside chainxe2x80x9d with reference to an amino acid or amino acid residue means a group attached to the xcex1-carbon atom of the xcex1-amino acid. For example, the R-group side chain for glycine is hydrogen, for alanine it is methyl, for valine it is isopropyl. For the specific R-groups or side chains of the xcex1-amino acids reference is made to A. L. Lehninger""s text on Biochemistry (see chapter 4).
The term xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9c(tower)alkylxe2x80x9d as used herein, either alone or in combination with another radical, means acyclic, straight chain or branched alkyl radicals containing up to ten carbon atoms and includes, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl. Likewise, the terms xe2x80x9cC1-3 alkylxe2x80x9d xe2x80x9cC1-4 alkylxe2x80x9d, xe2x80x9cC1-10 alkylxe2x80x9d and C1-16 alkyl are used to denote alkyl radicals containing up to three, four, ten and sixteen carbon atoms, respectively.
The term xe2x80x9chaloxe2x80x9d as used herein means a halogen radical selected from bromo, chloro, fluoro or iodo.
The term xe2x80x9cC1-6 haloalkylxe2x80x9d as used herein means a C1-6 alkyl as defined hereinabove wherein one or more of the hydrogen atom of the alkyl radical is replaced by a halogen atom. Such a haloalkyl is, for example, trifluoromethyl e.g. CF3.
The term xe2x80x9cC3-7 cycloalkylxe2x80x9d as used herein, either alone or in combination with another radical, means a cycloalkyl radical containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term xe2x80x9cC4-10 (alkylcycloalkyl) as used herein means a cycloalkyl radical containing from three to seven carbon atoms linked to an alkyl radical, the linked radicals containing up to ten carbon atoms; for example, cyclopropylmethyl, cyclopentylethyl, cyclohexylmeihyl, cyclohexylethyl or cycloheptylethyl. The term alkylcycloalkyl also refers a substituent such as: 
The term xe2x80x9cC2-6 alkenylxe2x80x9d as used herein, either alone or in combination with another radical, means an alkyl radical as defined above containing from 2 to 6 carbon atoms, and further containing at least one double bond. For example alkenyl includes allyl or vinyl.
The term xe2x80x9cC2-6 alkynylxe2x80x9d as used herein, either alone or in combination with another radical, means an alkyl radical as defined above containing from 2 to 6 carbon atoms, and further containing at least one triple bond.
The term xe2x80x9cC2-4 alkylenexe2x80x9d as used herein means a divalent alkyl radical derived by the removal of two hydrogen atoms from a straight or branched chain aliphatic hydrocarbon containing from three to four carbon atoms and includes, for example, xe2x80x94CH2CH2CH2xe2x80x94, CH(CH3)CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2xe2x80x94 and xe2x80x94CH2CH2CH2CH2xe2x80x94.
The term xe2x80x9cC1-6 alkanoylxe2x80x9d as used herein, either alone or in combination with another radical, means straight or branched 1-oxoalkyl radicals containing one to six carbon atoms and includes formyl, acetyl, 1-oxopropyl(propionyl), 2-methyl-1-oxopropyl, 1-oxohexyl and the like.
The term xe2x80x9cC1-6 alkoxyxe2x80x9d as used herein, either alone or in combination with another radical, means the radical xe2x80x94Oxe2x80x94C1-6 alkyl wherein alkyl is as defined above containing up to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter radical is known commonly as tert-butoxy.
The term xe2x80x9cC3-7 cycloalkoxyxe2x80x9d as used herein, either alone or in combination with another radical, means a C3-7 cycloalkyl group linked to an oxygen atom, such as, for example: 
The term xe2x80x9cC6 or C10 arylxe2x80x9d as used herein, either alone or in combination with another radical, means either an aromatic monocyclic system containing 6 carbon atoms or an aromatic bicyclic system containing 10 carbon atoms. For example, aryl includes phenyl or naphthyl.
The term xe2x80x9cC7-16 aralkylxe2x80x9d as used herein, either alone or in combination with another radical, means an aryl as defined above linked through an alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. Aralkyl includes for example benzyl, and butylphenyl.
The term xe2x80x9camino aralkylxe2x80x9d as used herein, either alone or in combination with another radical, means an amino group substituted with a C7-16 aralkyl group, such as, for example, the amino aralkyl: 
The term xe2x80x9ccarboxy(lower)alkylxe2x80x9d as used herein, either alone or in combination with another radical, means a carboxyl group (COOH) linked through a (lower)alkyl group as defined above and includes for example butyric acid or the groups: 
The term xe2x80x9ccyclicxe2x80x9d as used herein, either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a saturated or unsaturated cyclic hydrocarbon, containing from three to seven carbon atoms, unless otherwise indicated and optionally containing one or more heteroatom. The term cycle or cyclic, for example, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl,
The term xe2x80x9cbicyclicxe2x80x9d as used herein, either alone or in combination with another radical, means a monovalent radical derived from the fusion of two cycles as defined hereinabove. The term bicycle or bicyclic includes, for example, decalinyl, indenyl, and naphthyl.
The term xe2x80x9cunsaturated cycloalkylxe2x80x9d includes, for example, the cyclohexenyl: 
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cHetxe2x80x9d as used herein, either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur. Furthermore, xe2x80x9cHetxe2x80x9d as used herein, means a heterocycle as defined above fused to one or more other cycle be it a heterocycle or any other cycle. Examples of suitable heterocycles include: pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, thiazolo[4,5-b]-pyridine, quinoline, or indole, or the following heterocycles: 
The term xe2x80x9c(lower alkyl)-Hetxe2x80x9d as used herein, means a heterocyclic radical as defined above linked through a chain or branched alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. Examples of (lower alkyl)-Het include: 
The term xe2x80x9cpharmaceutically acceptable ester xe2x80x9d as used herein, either alone or in combination with another radical, means esters of the compound of formula I in which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, is replaced by an alkoxycarbonyl function: 
in which the R moiety of the ester is selected from alkyl (e.g. methyl, ethyl, n-propyl, t-butyl, nbutyl); alkoxyalkyl (e.g. methoxymethyl); alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl); aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl), optionally substituted with halogen, C1-4 alkyl or C1-4 alkoxy. Other suitable prodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith by reference, Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected in a mammal and transformed into the acid form of the compound of formula I.
With regard to the esters described above, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
In particular the esters may be a C1-16 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C1-6 alkyl, C1-6 alkoxy, nitro or trifluoromethyl.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein includes those derived from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na+, K+, and Ca++ salts are also contemplated to be within the scope of the invention (also see Pharmaceutical salts, Birge, S. M. et at., J. Pharm. Sci. (1977), 66, 1-19, incorporated herein by reference).
Included specifically within the scope of the compounds of formula I are racemates, diastereoisomers and optical isomers of compounds represented by formula IA: 
wherein Y is H or C1-6 alkyl; a is 0 or 1; b is 0 or 1; and
B is preferably an acyl derivative of formula R11C(O)xe2x80x94 wherein R11 is preferably C1-6 alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy or C1-6 alkoxy;,
C3-7 cycloalkyl optionally substituted with carboxyl, MeOC(O), EtOC(O) or BnOC(O);
3-carboxypropionyl (DAD); 4-carboxybutyryl (DAE); or 
More preferably, B is acetyl, 3-carboxypropionyl (DAD), 4-carboxylbutyryl (DAE), 
Still, more preferably, B is acetyl, DAD, DAE, 
Most preferably, B is acetyl.
The present invention comprises compounds of formula I or IA wherein preferably,
R6, when present, is the side chain of Asp or Glu.
Most preferably, R6, when present, is the side chain of Asp.
Alternatively, preferably, a is 0 and then R6 is absent.
The present invention comprises compounds of formula I or IA wherein preferably, R5, when present, is the side chain of an amino acid selected from the group consisting of: D-Asp, L-Asp, D-Glu, L-Glu, D-Val, L-Val, D-tert-butylglycine (Tbg), and L-Tbg.
More preferably, R5, when present, is the side chain of D-Asp, D-Val, or D-Glu.
Most preferably, R5, when present, is the side chain of D-Glu.
Alternatively, preferably a is 0 and b is 0, and then both R6 and R5 are absent.
The present invention comprises compounds of formula I or IA wherein preferably, R4 is isopropyl, cyclohexyl, 1-methytpropyl, 2-methylpropyl or tert-butyl,
More preferably; R4 is cyclohexyl or 1-methylpropyl.
Most preferably, R4 is cyclohexyl.
The present invention comprises compounds of formula I or IA wherein Z is preferably oxo.
The present invention comprises compounds of formula I or IA wherein preferably, R3 is the side chain of an amino acid selected from the group consisting of: Ile, allo-Ile, Chg, cyclohexylalanine (Cha), Val, Tbg or Glu
More preferably, R3 is the side chain of Val, Tbg or Chg.
Most preferably, R3 is the side chain of Val.
The present invention comprises compounds of formula I or IA wherein preferably, W is a group of formula II: 
wherein R2 is C1-8 alkyl; C1-8 alkyl substituted with carboxyl, C1-6 alkoxycarbonyl, benzyloxycarbonyl or benzylaminocarbonyl; C3-7 cyctoalkyl or benzyl.
Preferably, R2 is the side of chain of aminobutyric acid (Abu), Leu, Phe, Cha, Val, Ala, Asp, Glu, Glu(OBn), or Glu(NHBn).
Most preferably, R2 is the side chain of Asp, Abu or Val.
Still, more preferably, the invention comprises compounds of formula I wnerein W is a group of formula IIa: 
wherein preferably, X is CH or N.
Preferably R2a is a C3 or C4 alkylene (shown in bold) that joins X to form a 5- or 6-membered ring of formula III: 
R2a being optionally substituted at any position with R13, wherein X is CH or N; n is 1 or 2, and R13 is as defined below.
Most preferably, X is N. For example, preferably R2a is propyl joined to X wherein X is nitrogen to form a proline substituted with R13.
Most preferably R2 is the side chain of proline substituted at the 3-, 4-, or 5-position with R13, wherein R13 is as defined below.
Still, most preferably R2a is the side chain of proline (as shown in bold) substituted with R13 at the 4-position with the stereochemistry shown in formula IIIa: 
wherein R13 is Sxe2x80x94R12 or Oxe2x80x94R12 wherein R12 is preferably a C6 or C10 aryl, C7-15 aralkyl, Het or xe2x80x94CH2xe2x80x94Het, all optionally mono-, di- or tri-substituted with R15.
Preferably, R15 is C1-6 alkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; NO2; OH; halo; trifluoromethyl; carboxyl; C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with R16. More preferably, R15 is C1-6 alkyl; C1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; C6 or C10 aryl, or Het, said aryl or Het being optionally substituted with R16.
Preferably, R16 is C1-6 alkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; NO2; OH; halo; trifluoromethyl; or carboxyl. More preferably, R16 is C1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; halo; or trifluoromethyl.
Preferably, R13 is o-tolylmethoxy; m-tolylmethoxy; p-tolylmethoxy; (4-tert-butyl)methoxy; (3Ixe2x80x94Ph)CH2O; (4Brxe2x80x94Ph)O; (2Brxe2x80x94Ph)O; (3Brxe2x80x94Ph)O; (4Ixe2x80x94Ph)O; (3Brxe2x80x94Ph)CH2O; (3,5-Br2xe2x80x94Ph)CH2O; or R13 is OR12 or SR12 wherein R12 is C6 or C10 aryl, C7-16 aralkyl or Het, all optionally substituted with C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, acetylamido, nitro, CF3, NH2, OH, SH, halo, carboxyl, carboxy(lower)alkyl or a second aryl or aralkyl;
For example, R13 is preferably 1-naphthyloxy; 2-naphthyloxy; 1-naphthylmethoxy; 2-naphthylmethoxy; 
Further comprised within the invention are compounds of formula I or IA wherein R1a is preferably hydrogen and R1 is C1-6 alkyl optionally substituted with thiol. For example, R1 is preferably the side chain of the amino acid selected from the group consisting of: cysteine (Cys) aminobutyric acid (Abu), norvaline (Nva), or allylglycine (AlGly).
More preferably, R1a is H and R1 is propyl. For example, R1 is more preferably the side chain of the amino acid Nva.
Alternatively, preferably R1a and R1 together form a 3to 6-membered ring said ring being optionally substituted with R14. For example, R1a and R1 together form preferably a cyclopropyl optionally substituted with R14. For example, R1a and R1 together can be the side chain (shown in bold) of the following amino acid: 
referred to as 1-aminocyclopropylcarboxylic acid (Acca).
Preferably, R14 is methyl, ethyl, propyl, vinyl, allyl, benzyl, phenylethyl or phenylpropyl, all of which optionally substituted with halo. More preferably, R14 is ethyl, propyl, vinyl, bromovinyl or allyl. Most preferably, R14 is ethyl, vinyl or bromovinyl.
Further comprised in the present invention are compounds of formula I or IA wherein A is preferably hydroxy or a pharmaceutically acceptable salt or ester thereof; or C1-6 alkylamino, di(C1-6 alkyl)amino or phenyl-C1-6 alkylamino.
More preferably, A is hydroxy, or N(R17a)R17b wherein R17a and R17b are independently H, aryl or C1-6 alkyl optionally substituted with hydroxy or aryl.
Most preferably, A is OH, NH-benzyl or NHxe2x80x94CH(Me)Ph.
Still most preferably, A is OH or NHxe2x80x94CH(Me)-phenyl.
Specifically included within the scope of compounds of formula I or IA are racemates, diastereoisomers and optical isomers of compounds represented by formula IB: 
wherein
a, b, R6, R5, Y, R4, Z, R3, R14 and A are as defined above.
B is preferably R11xe2x80x94SO2 wherein R11 is preferably C6 or C10 aryl, a C7-16 aralkyl or Het all optionally substituted with C1-6 alkyl.
Alternatively, B is preferably H or an acyl derivative of formula R11C(O)xe2x80x94 wherein R11 is preferably C1-6 alkyl; C1-6 alkoxy, C3-7 cycloalkyl optionally substituted with hydroxy; amido optionally substituted with C1-6 alkyl or Het; C6 or C10 aryl, C7-16 aralkyl or Het all optionally substituted with C1-6 alkyl or hydroxy. More preferably, B is H or R11C(O)xe2x80x94 wherein R11 is more preferably C1-6 alkyl or Heterocycles such as: 
Most preferably, B is H; acetyl;
Included within the scope of the invention are compounds of formula IB wherein R13 is preferably o-tolylmethoxy; m-tolylmethoxy; p-tolyl methoxy; (4-tert-butyl)methoxy; (3Ixe2x80x94Ph)CH2O; (4Brxe2x80x94Ph)O; (2Brxe2x80x94Ph)O; (3Brxe2x80x94Ph)O; (4Ixe2x80x94Ph)O; (3Brxe2x80x94Ph)CH2O; (3,5-Brxe2x80x94Ph)CH2O; or R13 is OR12 or SR12 wherein R12 is C6 or C10 aryl, C7-16 aralkyl or Het, all optionally substituted with C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, acetylamido, nitro, CF3, NH2, OH, SH, halo, carboxyl, carboxy(lower)alkyl or a second aryl or aralkyl:
More preferably, R13 is preferably 1-naphthyloxy; 2-naphthyloxy; 1-naphthylmethoxy; 2-naphthylmethoxy; 2-, 3-, 4-, or 6-quinolinoxy, all optionally substituted.
Most preferably R13 is 1-naphthyloxy; 2-naphthyloxy; 1-naphthylmethoxy; 2-naphthylmethoxy; or substituted 4-quinolinoxy.
Even most preferably, R13 is 1-naphthylmethoxy; 2-naphthylmethoxy; benzyloxy, 1-naphthyloxy; 2-naphthyloxy; or quinolinoxy unsubstituted, mono- or di-substituted: with R15 as defined above. Most preferably, R13 is 1-naphtylmethoxy; or quinolinoxy unsubstituted, mono- or di-substituted with R15 as defined above.
Still, most preferably, R13 is: 
More preferably, R15A is amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl or Het; or C6 or C10 aryl or Het optionally substituted with R16. Most preferably, R15A is C6 or C10 aryl or Het, all optionally substituted with R16. Most preferably, R16 is amino; di(lower alkyl)amino; or (lower alkyl)amide. Even most preferably, R16 is amino; dimethylamino; or acetamido.
Even most preferably. R15A is C6 or C10 aryl or Het, all unsubstitulted.
Preferably, R15B is C1-6 alkyl; C1-6 alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; NO2; OH; halo; trifluoromethyl; or carboxyl. More preferably, R15B is C1-6 alkoxy; or di(lower alkyl)amino. Most preferably, R15B is methoxy.
As described hereinabove the P1 segment of the compounds of formula IB is a cyclopropyl ring system of formula: 
wherein C1 and C2 each represent an asymmetric carbon atom at positions 1 and 2 of the cyclopropyl ring. Notwithstanding other possible asymmetric centers at other segments of the compounds of formula I, the presence of these two asymmetric centers means that the compound of formula I can exist as racemic mixtures of diastereoisomers. As illustrated in the examples hereinafter the racemic mixtures can be prepared and thereafter separated into individual optical isomers, or these optical isomers can be prepared by chiral synthesis.
Hence, the compound of formula I can exist as a racemic mixture of diastereoisomers wherein R14 at position 2 is orientated syn to the carbonyl at position 1, represented by the radical: 
or the compound of formula I can exist as a racemic mixture of diastereoisomers wherein R14 at position 2 is orientated anti to the carbonyl at position 1, represented by the radical: 
In turn the racemic mixtures can be separated into individual optical isomers. A most interesting finding of this invention pertains to the spatial orientation of the P1 segment. The finding concerns the configuration of the asymmetric carbon at position 1. A preferred embodiment is one wherein asymmetric carbon at position 1 has the R configuration. 
More explicitly, when carbon 1 has the R configuration, HCV NS3 protease inhibition is further enhanced by the position of the substituent R14 (e.g. alkyl or alkylene) at carbon 2 of the cyclopropyl ring. A most preferred compound is an optical isomer having the R14 substituent and the carbonyl in a syn orientation in the following absolute configuration: 
In the case where R14 is ethyl, for example, the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration.
By way of illustrating the role of the absolute configuration of the substituent on the level of potency of the compound, compound 513 (Table 5) having the absolute configuration as 1R,2R, has an IC50 of 1.6 xcexcM whereas the corresponding 1S,2S isomer (compound 514) has an IC50 of 27.5 xcexcM. Therefore, the 1R,2R isomer is 25 fold more potent than the corresponding 1S,2S isomer.
Further specifically included within the scope of compounds of formula I are racemates, diastereoisomers and optical isomers of compounds represented by formula IC: 
wherein R4, R3, W, R1a, R1 and A are as defined above, and
B is preferably an amide of formula R11aN(R11b)C(O)xe2x80x94 wherein R11a is preferably C1-6 alkyl; C3-6 cycloalkyl; C3-7 (alkylcycloalkyl) optionally substituted with carboxy; C1-3 carboxyalkyl; C6 aryl; C7-10 arylalkyl; 2-tetrahydrofuranylmethyl; or 2-thiazolidylmethyl;
and R11b is preferably C1-4 alkyl substituted with carboxyl.
More preferably, B is R11aN(R11b)xe2x80x94C(O)xe2x80x94 wherein R11a is preferably cyclopropylmethyl, isopropyl, carboxyethyl, benzylmethyl, benzyl, or 2-tetrahydrofuranylmethyl. More preferably R11b is C1-4 alkyl substituted with carboxyl.
Most preferably, R11b is ethyl carboxyl.
Specifically comprised in the scope of the invention are compounds of formula I wherein Q is CH2, a is 0, b is 0, and B is an amide of formula R11aN(R11b)xe2x80x94C(O)xe2x80x94 wherein R11a is C1-6 alkyl, C3-6 cycloalkyl, C3-7 (alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl, phenyl, C7-10 arylalkyl,
2-tetrahydrofuranylmethyl, or 2-thiazolidylmethyl;
and R11b is phenyl; or C1-6 alkyl substituted with carboxyl or C1-4 carboxyalkyl; or
Q is Nxe2x80x94Y wherein Y is H or C1-6 alkyl; a is 0 or 1; b is 0 or 1; and B is an acyl derivative of formula R11xe2x80x94C(O)xe2x80x94 wherein R11 is (i) C1-6 alkyl, C1-6 alkyl substituted with carboxyl, MeC(O)Oxe2x80x94, MeOxe2x80x94, EtOxe2x80x94, MeCH2CH2Oxe2x80x94 or Me3Cxe2x80x94Oxe2x80x94, (ii) cyclopentyl or cyclohexyl optionally substituted with carboxyl; (iv) C4-10 (alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl;
(v) 
xe2x80x83or (vi) phenyl, benzyl or phenylethyl;
R5, when present, is CH2COOH or CH2CH2COOH;
R5, when present, is C1-6 alkyl or CH2COOH or CH2CH2COOH;
and when Q is either CH2 or Nxe2x80x94Y,
R4 is C1-6 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
Z is oxo or thio;
R3 is C1-6 alkyl; C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
W is a group of formula II wherein R2 is C1-10 alkyl, C3-10 cycloalkyl, C7-11 aralkyl; CH2COOH or CH2CH2COOH; or W is a group of formula IIxe2x80x2 wherein X is N or CH and R2 is the divalent radical xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94 which together with X and the carbon atom to which X and R2 are attached form a 5- or 6-membered ring, said ring optionally substituted with R13 wherein
R13 is Sxe2x80x94R12 or Oxe2x80x94R12 wherein R12 is a C6 or C10 aryl, C7-16 aralkyl, Het or xe2x80x94CH2xe2x80x94Het, all optionally mono-, di- or tri-substituted with R15, wherein
R15 is C1-6 alkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; NO2; OH; halo; trifluoromethyl; carboxyl; C6 or C10 aryl, C7-16 aralkyl, or Het, said aryl, aralkyl or Het being optionally substituted with
R16, and wherein
R16 is C1-6 alkyl; C1-6 alkoxy; amino; mono- or di-(lower alkyl)amino; (lower alkyl)amide; NO2; OH; halo; trifluoromethyl; or carboxyl.
R1a is hydrogen and R1 is methyl, thiomethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-(methylthio)ethyl or 2-propylene; or R1a and R1 together with the carbon atom to which they are attached form a cyclopropyl which may optionally be substituted with C1-8 alkyl; and
A is hydroxy or a pharmaceutically acceptable salt thereof; C1-6 alkoxy, or (aryl C1-6-alkoxy).
Also comprised within the scope of the present invention are compounds of formula I:
wherein B is an acyl derivative of formula R11xe2x80x94C(O)xe2x80x94 wherein R11 is C1-10 alkyl optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl; or a C4-10 (alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl; or R11 is C6 or C10 aryl or C7-16 aralkyl optionally substituted with a C1-6 alkyl:
a is 0 or 1;
R6, when present, is C1-6 alkyl optionally substituted with carboxyl;
b is 0 or 1;
R5, when present, is C1-6 alkyl optionally substituted with carboxyl;
Q is Nxe2x80x94Y wherein Y is H or C1-6 alkyl;
R4 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
Z is oxo;
R3 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
W is a group of formula II: 
xe2x80x83wherein R2 is C1-6 alkyl; C1-6 alkyl optionally substituted with carboxyl; C6 or C10 aryl; or C7-16 aralkyl;
W is a group of formula IIa: 
xe2x80x83wherein X is CH or N; and
R2a is C3-4 alkyl that joins X to form a 5- or 6-membered ring, said ring optionally substituted with R13 OH; SH; NH2; carboxyl; R12; CH2xe2x80x94R12, OR12, SR12, NHR12 or NR12R12a wherein R12 and R12a are independently:
a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R15,
or R12 or R12a is a C6 or C10 aryl or C7-16 aralkyl optionally mono-, di- or tri-substituted with R15,
or R12 or R12a is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R15,
wherein each R15 is independently C1-6 alkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-16 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R16;
wherein R16 is C1-6 alkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide; or (lower alkyl)amide; and
R1a is hydrogen, and R1 is C1-6 alkyl optionally substituted with thiol, or C2-6 alkenyl; or
R1a and R1 together form a 3- to 6-membered ring optionally substituted with C1-6 alkyl; and
A is OH or a pharmaceutically acceptable salt or ester thereof.
Further comprised in the scope of the invention are compounds of formula IA, wherein B is an acyl derivative of formula R11xe2x80x94C(O)xe2x80x94 wherein R11 is C1-6 alkoxy, C1-10 alkyl optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl or benzylcarboxy; or 
R6 is absent;
R5 is absent;
Y is H;
R4 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
Z is oxo;
R3 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
W is a group of formula II: 
xe2x80x83wherein R2 is C1-6 alkyl; C3-6 cycloalkyl; C1-6 alkyl substituted with carboxyl; C6 or C10 aryl; or C7-11 aralkyl; or
W is a group of formula IIa: 
xe2x80x83wherein X is N; and R2a is C3-4 alkyl that joins X to form a 5- or 6-membered ring, said ring optionally substituted with OH; SH; NH2; carboxyl; R12; CH2xe2x80x94R12, OR12, SR12, NHR12 or NR12R12a wherein R12 and R12a are independently:
a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R15,
or R12 or R12a is a C6 or C10 aryl or C7-16 aralkyl optionally mono-, di- or tri-substituted with R15,
or R12 or R12a is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R15,
wherein each R15 is independently C1-6 alkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-16 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R16;
wherein R16 is C1-6 alkyl; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide: or (lower alkyl)amide;
R1a is H and R1 is the side chain of Cys, Abu, Nva or allylglycine; or
R1a and R1 together with the carbon atom to which they are attached form a cyclopropyl; and A is or a pharmaceutically acceptable salt thereof; methoxy, ethoxy, phenoxy, or benzyloxy.
Also comprised in the scope of the invention are compounds of formula IA, wherein B is acetyl, 3-carboxypropionyl, 4-carboxylbutyryl, AcOCH2C(O), Me3COC(O). 
Y is H or Me, a is 0 or 1, b is 0 or 1,
R6, when present, is the side chain of Asp or Glu,
R5, when present, is the side chain of Asp, D-Asp, Glu, D-Glu, Val, D-Val or Tbg,
R4 is the side chain of Val, Chg, Tbg, Ile or Leu,:
Z is oxo or thioxo,
R3 is hydrogen or the side chain of Ile, Chg, Val, Glu;
W is Abu, Leu, Phe, Val, Ala, Glu, Glu(OBn); or
W is group of formula IIIa: 
xe2x80x83wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, Oxe2x80x94Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, (4-tert-butyl)benzyloxy, (3Ixe2x80x94Ph)CH2O, (4Brxe2x80x94Ph)O, (2Brxe2x80x94Ph)O, (3Brxe2x80x94Ph)O, (4Ixe2x80x94Ph)O, (3Brxe2x80x94Ph)CH2O, (3,5-Br2xe2x80x94Ph)CH2O, 
R1a is H and R1 is the side chain of Cys, Abu, Nva or allylglycine; or
R1a and R1 together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxyl, or a pharmaceutically acceptable salt or ester thereof.
A further preferred embodiment of the invention comprises compounds of formula IB: 
wherein
a is 0 or 1; b is 0 or 1; Y is H or C1-6 alkyl; and z is oxo;
B is H, an acyl derivative of formula R11xe2x80x94C(O)xe2x80x94 or a sulfonyl of formula R11xe2x80x94SO2 
wherein
R11 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy or C1-6 alkoxy;
(ii) C3-7 cycloalkyl optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl or phenylmethoxycarbonyl;
(iii) C6 or C10 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, hydroxy, or amino optionally substituted with C1-6 alkyl; or
(iv) Het optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, or amido optionally substituted with C1-6 alkyl;
R6, when present, is C1-6 alkyl substituted with carboxyl;
R5, when present, is C1-6 alkyl optionally substituted with carboxyl;
R4 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
R3 is C1-10 alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
R13 is CH2xe2x80x94R12, NHxe2x80x94R12, Oxe2x80x94R12 or Sxe2x80x94R12, wherein R12 is a saturated or unsaturated C3-7 cycloalkyl or C4-10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R15,
or R12 is a C6 or C10 aryl or C7-16 aralkyl optionally mono-, di- or tri-substituted with R15,
or R12 is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R15, wherein each R15 is independently C1-6 alkyl, C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfony; NO2; OH; SH; halo; haloalkyl: amido optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 aryl, C7-16 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R16;
wherein R16 is C1-6 alkyl; C1-6 alkoxy: amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide; or (lower alkyl)amide;
R14 is C1-6 alkyl or C2-6 alkenyl optionally substituted with halogen; and
A is hydroxy or a N-substituted amino, or a pharmaceutically acceptable salt or ester thereof.
Further included in the scope of the invention are compounds of formula IB, wherein.
B is H, lower alkyl-C(O)xe2x80x94 or Hetxe2x80x94C(O)xe2x80x94;
R6, when present, is the side chain of Asp or Glu;
R5, when present, is the side chain of D- or L-: Asp, Glu, Val, or Tbg;
Y is H or methyl;
R4 is the side chain of Val, Chg, Tbg, Ile or Leu;
R3 is the side chain of Ile, Chg, Val or Tbg;
R13 is Bn, PhCH2CH2, PhCH2CH2CH2, Oxe2x80x94Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, (4-tert-butyl)benzyloxy, (3Ixe2x80x94Ph)CH2O, (4Brxe2x80x94Ph)O, (2Brxe2x80x94Ph)O, (3Brxe2x80x94Ph)O, (4Ixe2x80x94Ph)O, (3Brxe2x80x94Ph)CH2O, (3,5-Br2xe2x80x94Ph)CH2O. 
xe2x80x83wherein R15A is amido optionally monosubstituted with C1-6 alkyl C6 or C10 aryl, C7-16 aralkyl or Het; or C6 or C10 aryl or Het optionally substituted with R16, and R16 is amino; di(lower alkyl)amino; or (lower alkyl)amide.
P1 is a cyclopropyl ring system of formula 
xe2x80x83wherein R14 is ethyl, vinyl or bromovinyl; and
A is hydroxy or N(R17a)R17b wherein R17a and R17b are independently H, aryl or C1-6 alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutically acceptable salt or ester thereof.
A further preferred group of compounds is represented by formula IB wherein B is H, acetyl or Hetxe2x80x94C(O)xe2x80x94; R6, when present, is the side chain of Asp; R5, when present, is the side chain of D-Asp, D-Glu or D-Val; Y is H; R4 is the side chain of Chg or Ile; R3 is the side chain of Val, Chg or Tbg; R13 is 1-naphthylmethoxy, benzyloxy, 4-quinolinoxy, or 
P1 is a cyclopropyl ring system of formula 
xe2x80x83wherein R14 is Et or xe2x80x94CHxe2x95x90CH2 or xe2x80x94CHxe2x95x90CHBr; and
A is hydroxy or xe2x80x94NHxe2x80x94(S)CH(Me)Ph,
or a pharmaceutically acceptable salt or ester thereof.
An even further preferred group of compounds is represented by formula IB wherein
B is acetyl; R6, when present, is the side chain of Asp: R5, when present is the side chain of D-Glu; Y is H; R4 is the side chain of Chg; R3 is the side chain of Val or Tbg; R13 is: 
A is hydroxy, or a pharmaceutically acceptable salt or ester thereof.
Further comprised in the scope of the invention are compounds of formula IC. wherein B is an amide of formula R11aN(R11b)xe2x80x94C(O)xe2x80x94 wherein I11a is C1-6 alkyl, C3-6 cycloalkyl, C3-7 (alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl, phenyl, C7-10 arylalkyl, 2-tetrahydrofuranyimethyl, or 2-thiazolidylmethyl; and R11b is phenyl; or C1-6 alkyl substituted with carboxyl or C1-4 carboxyalkyl;
R4 is cyclohexyl:
Z is oxo;
R3 is hydrogen or the side chain of Ile, Chg, Val, Glu;
W is Abu, Leu, Phe, Val, Ala, Glu, Glu(OBn); or
W is group of formula IIIa: 
xe2x80x83wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, Oxe2x80x94Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, (4-tert-butyl)methoxy, (3Ixe2x80x94Ph)CH2O, (4Brxe2x80x94Ph)O, (2Brxe2x80x94Ph)O, (3Brxe2x80x94Ph)O, (4Ixe2x80x94Ph)O, (3Brxe2x80x94Ph)CH2O, (3.5-Br2xe2x80x94Ph)CH2O, 
R1a is H and R1 is the side chain of Cys, Abu, Nva or allylglycine; or
R1a and R1 together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxy, or a pharmaceutically acceptable salt or ester thereof.
Finally, specifically included in the scope of the invention are all compounds of formula I presented in Tables 1 to 10.
According to an alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise another anti-HCV agent. Examples of anti-HCV agents include xcex1- or xcex2-interferon, ribavirin and amantadine.
According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise other inhibitors of HCV protease.
According to yet another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an inhibitor of other targets in the HCV life cycle, including but not limited to, such as helicase, polymerase, metalloprotease or internal ribosome entry site (IRES).
The pharmaceutical compositions of this invention may be administered orally, parenterally or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween(copyright) 80) and suspending agents.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions in the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired certain sweetening and/or flavoring and/or coloring agents may be added.
Other suitable vehicles or carriers for the above noted formulations and compositions can be found in standard pharmaceutical texts, e.g. in xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Penn., (1995).
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day, as a continuous infusion, or alternatively, as a once-a-week slow release formulation. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient""s disposition to the infection and the judgment of the treating physician. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the peptide. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
When the compositions of this invention comprise a combination of a compound of formula I and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen or as combination therapy as described below
When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition may be administered in vivo to mammals, such as man, to inhibit HCV NS3 protease or to treat or prevent HCV virus infection. Such treatment may also be achieved using the compounds of this invention in combination with agents which include, but are not limited to: immunomodulatory agents such as xcex1-, xcex2-, or xcex3-interferons; other antiviral agents such as ribavirin, amantadine; other inhibitors of HCV NS3 protease; inhibitors of other targets in the HCV life cycle such as helicase, polymerase, metalloprotease, or internal ribosome entry; or combinations thereof. The additional agents may be combined with the compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
Accordingly, another embodiment of this invention provides methods of inhibiting HCV NS3 protease activity in mammals by administering a compound of the formula I, wherein the substituents are as defined above.
In a preferred embodiment, these methods are useful in decreasing HCV NS3 protease activity in a mammal. If the pharmaceutical composition comprises only a compound of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an agent selected from an immunomodulatory agent, an antiviral agent, a HCV protease inhibitor, or an inhibitor of other targets in the HCV life cycle such as helicase, polymerase, metalloprotease or IRES. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the compositions of this invention.
In an alternate preferred embodiment, these methods are useful for inhibiting viral replication in a mammal. Such methods are useful in treating or preventing HCV disease. If the pharmaceutical composition comprises only a compound of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an agent selected from an immunomodulatory agent, an antiviral agent, a HCV protease inhibitor, or an inhibitor of other targets in the HCV life cycle. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the composition according to this invention.
The compounds set forth herein may also be used as laboratory reagents. The compounds of this invention may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials).
The compounds set forth herein may also be used as research reagents. The compounds of this invention maybe used as positive control to validate surrogate cell-based assays or in vitro or in vivo viral replication assays.
The compounds of the present invention were synthesized according to the process as illustrated in scheme I (wherein CPG is a carboxyl protecting group. APG is an amino protecting group and a is an amine) 
Briefly, the P1, P2, P3, P4, and optionally P5 and P6 can be linked by well known peptide coupling techniques. The P1, P2, P3, P4, and P5 and P6 groups may be linked together in any order as long as the final compound corresponds to peptides of formula 1. For example, P6 can be linked to P5 to give P5-P6 that is linked to P4-P3-P2-P1; or P6 linked to P5-P4-P3-P2 then linked to an appropriately C-terminal protected P1.
Generally, peptides are elongated by deprotecting the (xcex1-amino group of the N-terminal residue and coupling the unprotected carboxyl group of the next suitably N-protected amino acid through a peptide linkage using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in stepwise fashion, as depicted in Scheme I, or by condensation of fragments (two or several amino acids), or combination of both processes, or by solid phase peptide synthesis according to the method originally described in Merrifield, J. Am. Chem. Soc. (1963), 85, 2149-2154, the disclosure of which is hereby incorporated by reference.
Coupling between two amino acids, an amino acid and a peptide, or two peptide fragments can be carried out using standard coupling procedures such as the azide method, mixed carbonic-carboxylic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, Woodward reagent K-method, carbonyldiimidazole method, phosphorus reagents or oxidation-reduction methods. Some of these methods (especially the carbodiimide method) can be enhanced by adding 1-hydroxybenzotriazole. These coupling reactions can be performed in either solution (liquid phase) or solid phase.
More explicitly, the coupling step involves the dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of a coupling agent to form a linking amide bond. Descriptions of such coupling agents are found in general textbooks on peptide chemistry for example. M. Bodanszky, xe2x80x9cPeptide Chemistryxe2x80x9d, 2nd rev ed., Springer-Verlag, Berlin, Germany, (1993). Examples of suitable coupling agents are N,Nxe2x80x2dicyclohexylcarbodiimide, 1-hydroxybenzotriazole in the presence of N,Nxe2x80x2-dicyclohexylcarbodiimide or N-pethyl-Nxe2x80x2[(3-dimethylamino)propyl]carbodiimide. A very practical and useful coupling agent is the commercially available (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole. Another very practical and useful coupling agent is commercially available 2-(1H-benzotriazol-1-yl)-N, N, Nxe2x80x2, Nxe2x80x2-tetramethyluronium tetrafluoroborate. Still another very practical and useful coupling agent is commercially available O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2Nxe2x80x2-tetramethyiuronium hexafluorophosphate.
The coupling reaction is conducted in an inert solvent, e.g. dichloromethane, acetonitrile or dimethylformamide. An excess of a tertiary amine, e.g. diisopropylethylamine. N-methylmorpholine or N-methylpyrrolidine, is added to maintain the reaction mixture at a pH of about 8. The reaction temperature usually ranges between 0xc2x0 C. and 50xc2x0 C. and the reaction time usually ranges between 15 min and 24 h.
When a solid phase synthetic approach is employed, the C-terminal carboxylic acid is attached to an insoluble carrier (usually polystyrene). These insoluble carriers contain a group that will react with the carboxylic group to form a bond that is stable to the elongation conditions but readily cleaved later. Examples of which are: chloro- or bromomethyl resin, hydroxymethyl resin, and aminomethyl resin. Many of these resins are commercially available with the desired C-terminal amino acid already incorporated. Alternatively, the amino acid can be incorporated on the solid support by known methods Wang, S.-S., J. Am. Chem. Soc., (1973), 95, 1328; Atherton, E.; Shepard, R. C. xe2x80x9cSolid-phase peptide synthesis; a practical approachxe2x80x9d IRL Press: Oxford, (1989); 131-148. In addition to the foregoing, other methods of peptide synthesis are described in Stewart and Young, xe2x80x9cSolid Phase Peptide Synthesisxe2x80x9d, 2nd ed., Pierce Chemical Co., Rockford, Ill. (1984); Gross, Meienhofer, Udenfriend, Eds., xe2x80x9cThe Peptides: Analysis, Synthesis, Biologyxe2x80x9d, Vol. 1, 2, 3, 5, and 9, Academic Press, New-York, (1980-1987); Bodansky et al., xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d Springer-Verlag, New-York (1984), the disclosures of which are hereby incorporated by reference.
The functional groups of the constituent amino acids generally must be protected during the coupling reactions to avoid formation of undesired bonds. The protecting groups that can be used are listed in Greene, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, New York (1981) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biologyxe2x80x9d, Vol. 3, Academic Press, New York (1981), the disclosures of which are hereby incorporated by reference.
The xcex1-carboxyl group of the C-terminal residue is usually protected as an ester (PG1) that can be cleaved to give the carboxylic acid. Protecting groups that can be used include: 1) alkyl esters such as methyl, trimethylsilylethyl and t-butyl, 2) aralkyl esters such as benzyl and substituted benzyl, or 3) esters that can be cleaved by mild base treatment or mild reductive means such as trichloroethyl and phenacyl esters.
The xcex1-amino group of each amino acid to be coupled to the growing peptide chain must be protected (PG2). Any protecting group known in the art can be used. Examples of such groups include: 1) acyl groups such as formyl trifluoroacetyl, phthalyl, and prtoluenesulfonyl; 2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl such as trimethylsilyl; and 7) thiol containing groups such as phenylthiocarbonyl and dithiasuccinoyl. The preferred xcex1-amino protecting group is either Boc or Fmoc. Many amino acid derivatives suitably protected for peptide synthesis are commercially available.
The xcex1-amino protecting group of the newly added amino acid residue is cleaved prior to the coupling of the next amino acid. When the Boc group is used, the methods of choice are trifluoroacetic acid, neat or in dichloromethane, or HCl in dioxane or in ethyl acetate. The resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or substituted piperidine in dimethylformamide, but any secondary amine can be used. The deprotection is carried out at a temperature between 0xc2x0 C. and room temperature (RT), usually 20-22xc2x0 C.
Any of the amino acids having side chain functionalities must be protected during the preparation of the peptide using any of the above-described groups. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depend upon the amino acid and presence of other protecting groups in the peptide. The selection of such protecting groups is important in that the group must not be removed during the deprotection and coupling of the xcex1-amino group.
For example, when Boc is used as the xcex1-amino protecting group, the following side chain protecting groups are suitable: ptoluenesulfonyl (tosyl) moieties can be used to protect the amino side chain of amino acids such as Lys and Arg; acetamidomethyl, benzyl (Bn), or t-butylsulfonyl moieties can be used to protect the sulfide containing side chain of cysteine; benzyl (Bn) ethers can be used to protect the hydroxy containing side chains of serine, threonine or hydroxyproline; and benzyl esters can be used to protect the carboxy containing side chains of aspartic acid and glutamic acid.
When Fmoc is chosen for the a-amine protection, usually tert-butyl based protecting groups are acceptable. For instance, Boc can be used for lysine and arginine, tert-butyl ether for serine, threonine and hydroxyproline, and tert-butyl ester for aspartic acid and glutamic acid. Triphenylmethyl (Trityl) moiety can be used to protect the sulfide containing side chain of cysteine.
When A is an amide, P1 is coupled to an appropriate amine (a) prior to the coupling to P2. Such amination will be readily recognized by persons skilled in the art. Once the elongation of the peptide is completed all of the protecting groups are removed. When a liquid phase synthesis is used, the protecting groups are removed in whatever manner is dictated by the choice of protecting groups. These procedures are well known to those skilled in the art.
When a solid phase synthesis is used, the peptide is cleaved from the resin simultaneously with the removal of the protecting groups. When the Boc protection method is used in the synthesis, treatment with anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole, or pcresol at 0xc2x0 C. is the preferred method for cleaving the peptide from the resin. The cleavage of the peptide can also be accomplished by other acid reagents such as trifluoromethanesulfonic acid/trifluoroacetic acid mixtures. If the Fmoc protection method is used, the N-terminal Fmoc group is cleaved with reagents described earlier. The other protecting groups and the peptide are cleaved from the resin using solution of trifluoroacetic acid and various additives such as anisole, etc.
When Q is CH2, a is 0, b is 0 and B is R11aN(R11b)C(O), the compounds were prepared according to a method analogous to the general method described for the peptides in Scheme I using a readily available succinyl intermediate, t-BuO-C(O)CH2CH(R4)xe2x80x94CO-PG1 (e.g. PG 1=2-oxo-4-substituted-oxazolidin-3-yl). This succinyl intermediate can easily be prepared according to the method of Evans"" et al (J. Am. Chem. Soc. (1982), 104, 1737) using the appropriate 4-substituted-3-acyl-2-oxazolidinone in the presence of a strong base such as lithium diisopropylamide or sodium bis(trimethylsilyl)amide and t-butyl bromoacetate. After cleavage of the 2-oxazolidinone moiety with LiOOH (Evans"" et al., Tetrahedron Lett. (1987), 28, 6141), the resulting acid was coupled to the P3-P2-P1-PG1 segment to give t-BuO-C(O)xe2x80x94CH2CH(R4)xe2x80x94CO-P3-P2-P1-PG1. The latter was treated with hydrogen chloride to selectively convert the terminal t-butyl ester into the corresponding acid that was finally coupled to R11aNH(R11b) to give, after removal of the protective group(s), the desired peptide derivative. The amines R11aNH(R11b) are commercially available or the synthesis is well known in the art. A specific embodiment of this process is presented in Example 23.
Alternatively, starting with the same succinyl intermediate (t-BuO-C(O)CH2CH(R4)xe2x80x94CO-PG1), the sequence of reactions can be inverted to introduce first R11aNH(R11b) and then P3-P2-P1-PG1 to give the desired peptide derivative.
Synthesis of capping group B and P6, P5, P4, and P3 moieties Different capping groups B are introduced to protected P6, P5, P4, the whole peptide or to any peptide segment with an appropriate acyl chloride or sultonyl chloride that is either available commercially or for which the synthesis is well known in the art.
Different P6 to P3 moieties are available commercially or the synthesis is well known in the art.
1.1 Synthesis of Orecursors:
A) Synthesis of haloarylmethane derivatives.
The preparation of halomethyl-8-quinoline IId was done according to the procedure of K. N. Campbell et al., J. Amer. Chem. Soc., (1946), 68, 1844. 
Briefly, 8-quinoline carboxylic acid IIa was converted to the corresponding alcohol IIc by reduction of the corresponding acyl halide IIb with a reducing agent such as lithium aluminium hydride. Treatment of alcohol IIb with the appropriate hydrohaloacid gives the desired halo derivative IId. A specific embodiments of this process is presented in Example 1A.
B) Synthesis of aryl alcohols derivatives:
2-phenyl-4-hydroxyquinoline derivatives IIIc were prepared according to Giardina et al. (J. Med. Chem., (1997), 40, 1794-1807). 
R16 and R15B=alkyl, OH, SH, halo, NH2, NO2.
Benzoylacetamide (IIIa) was condensed with the appropriate aniline (IIIb) and the imine obtained was cyclized with polyphosphoric acid to give the corresponding 2-phenyl-4-hydroxyquinoline (IIIc). A specific embodiment of this process is presented in Example 1B and 1C.
1.2 Synthesis of P2:
A) The synthesis of 4-substituted proline (wherein R13 is attached to the ring via a carbon atom) (with the stereochemistry as shown). 
is done as shown in Scheme IV according to the procedures described by J. Ezquerra et al. (Tetrahedron, (1993), 38, 8665-8678) and C. Pedregal et al. (Tetrahedron Lett., (1994), 35, 2053-2056). A specific embodiment of this process is presented in Example 2. 
Briefly, Boc-pyroglutamic acid is protected as a benzyl ester. Treatment with a strong base such as lithium diisopropylamide followed by addition of an alkylating agent (Brxe2x80x94R12 or Ixe2x80x94R12) gives the desired compounds IVe after reduction of the amide and deprotection of the ester.
B) The synthesis of O-substituted 4-(R)-hydroxyproline: 
may be carried out using the different processes described below.
When R12 is aryl, Het, aralkyl, or (lower alkyl)-Het, the process can be carried out according to the procedure described by E. M. Smith et al. (J. Med. Chem. (1988), 31, 875-885). Briefly, commercially available Boc-4(R)hydroxyproline is treated with a base such as sodium hydride or K-tBuO and the resulting alkoxide reacted with an halo-R12 (Brxe2x80x94R12, Ixe2x80x94R12, etc.,) to give the desired compounds. Specific embodiments of this process are presented in Examples 3, 4A and 4B C) Alternatively, when R12 is aryl or Het, the compounds can also be prepared via a Mitsunobu reaction (Mitsunobu (1981), Synthesis, January, 1-28; Rano etal., (1995), Tet. Lett. 36(22), 3779-3792; Krchnak et al., (1995), Tet. Lett. 36(5), 62193-6196; Richter et al., (1994), Tet. Lett. 35(27), 4705-4706). Briefly, commercially available Boc-4(S)-hydroxyproline methyl ester is treated with the appropriate aryl alcohol or thiol in the presence of triphenylphosphine and diethylazodicarboxylate (DEAD) and the resulting ester is hydrolyzed to the acid. Specific embodiment of this process is presented in Example 5. 
Alternatively, the Mitsunobu reaction can be produced in solid phase (as shown in Scheme V). The 96-well block of the Model 396 synthesizer (advanced ChemTech) is provided with aliquots of resin-bound compound (Va) and a variety of aryl alcohols or thiols and appropriate reagents are added. After incubation, each resin-bound product (Vb) is washed, dried, and cleaved from the resin.
Furthermore, a Suzuki reaction (Miyaura et al., (1981), Synth. Comm. 11, 513; Sato et al., (1989), Chem. Lett., 1405; Watanabe et al., (1992), Synlett., 207; Takayuki et al., (1993), J. Org. Chem. 58, 2201; Frenette et al., (1994), Tet. Lett. 35(49), 9177-9180; Guiles et al., (1996), J. Org. Chem. 61, 5169-5171) can also be used to further functionalize the aryl substituent.
2.1 The synthesis was done according to scheme VI. 
a) Briefly, di-protected malonate VIa and 1,2-dihaloalkane VIb or cyclic sulfate VIc, (synthesized according to K. Burgess and Chun-Yen KE (Synthesis, (1996), 1463-1467) are reacted under basic conditions to give the diester VId.
b) A regioselective hydrolysis of the less hindered ester is performed to give the acid VIe.
c) This acid VIe is subjected to a Curtius rearrangement to give a racemic mixture of 1-aminocyclopropylcarboxylic acid derivatives VIf with R14 being syn to the carboxyl group. A specific embodiment for this synthesis is presented in Example 6.
d, e) Alternatively, selective ester formation from the acid VIe with an appropriate halide (P*Cl) or alcohol (P*OH) forms diester VIg in which the P* ester is compatible with the selective hydrolysis of the P ester. Hydrolysis of P ester provides acid VIh.
f) A Curtius rearrangement on VIh gives a racemic mixture of 1-aminocyclopropylcarboxylic acid derivatives VIi with R14 group being anti to the carboxyl group. A specific embodiment for this synthesis is presented in Example 11.
2.2 An alternative synthesis for the preparation of derivatives VIf (when R14 i vinil, syn to the carboxyl group) is described below. 
Treatment of commercially available imine VIIa with 1,4-dihalobutene VIIb in presence of a base produces, after hydrolysis of the resulting imine VIIc, VIId having the allyl substituent syn to the carboxyl group. This process is presented in Example 12.
Resolution of all of the above enantiomeric mixtures at carbon 1 (VIe and VIId) can be carried out via:
1) enzymatic separation (Examples 10 and 14);
2) crystallization with a chiral acid (Example 15); or
3) chemical derivatization (Example 7).
Following resolution, determination of the absolute stereochemistry can be carried out as presented in Example 8.
Resolution and stereochemistry determination can be carried out in the same manner for the enantiomeric mixtures at carbon 1 wherein the substituent at C2 is anti to the carboxyl group (VIi).
Accordingly, the invention further comprises a process for the preparation of a peptide analog of formula I, IA, IB or IC, wherein P1 is a substituted aminocyclopropyl carboxylic acid residue, comprising the step of: coupling a peptide selected from the group consisting of: APG-P6-P5-P4-P3-P2; APG-P5-P4-P3-P2; APG-P4-P3-P2; APG-P3-P2; and APG-P2; with a P1 intermediate of formula: 
wherein R14 is C1-6 alkyl or C2-6 alkenyl optionally substituted with halogen, CPG is a carboxyl protecting group and APG is an amino protecting group, and P6 to P2 are as defined above.
Finally, the invention also comprises the use of an intermediate of formula: 
wherein R14 is C1-6 alkyl or C2-6 alkenyl optionally substituted with halogen, CPG is a carboxyl protecting group and APG is an amino protecting group, for the preparation of a compound of formula I, IA, IB, or IC as defined above